EP0025232B1 - 4-(Substituierte Thiazolyl)-3-hydroxy-3-pyrrolin-2,5-dion-Verbindungen, Verfahren zur Herstellung und sie enthaltende pharmazeutische Zusammensetzung - Google Patents
4-(Substituierte Thiazolyl)-3-hydroxy-3-pyrrolin-2,5-dion-Verbindungen, Verfahren zur Herstellung und sie enthaltende pharmazeutische Zusammensetzung Download PDFInfo
- Publication number
- EP0025232B1 EP0025232B1 EP80105409A EP80105409A EP0025232B1 EP 0025232 B1 EP0025232 B1 EP 0025232B1 EP 80105409 A EP80105409 A EP 80105409A EP 80105409 A EP80105409 A EP 80105409A EP 0025232 B1 EP0025232 B1 EP 0025232B1
- Authority
- EP
- European Patent Office
- Prior art keywords
- pharmaceutically acceptable
- compounds
- compound
- acceptable salts
- pyrroline
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
- 239000008194 pharmaceutical composition Substances 0.000 title claims 2
- -1 4-(substituted thiazolyl)-3-hydroxy-3-pyrroline-2,5-dione compounds Chemical class 0.000 title abstract description 7
- 238000000034 method Methods 0.000 title description 11
- 150000001875 compounds Chemical class 0.000 claims description 38
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- 150000003839 salts Chemical class 0.000 claims description 16
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
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- 125000004432 carbon atom Chemical group C* 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 5
- 150000002367 halogens Chemical class 0.000 claims description 5
- 239000011541 reaction mixture Substances 0.000 claims description 5
- 150000002431 hydrogen Chemical class 0.000 claims description 4
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
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- 229960003459 allopurinol Drugs 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
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- 229910052786 argon Inorganic materials 0.000 description 1
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- 210000004369 blood Anatomy 0.000 description 1
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- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 229960004987 calcium carbimide Drugs 0.000 description 1
- MYFXBBAEXORJNB-UHFFFAOYSA-N calcium cyanamide Chemical compound [Ca+2].[N-]=C=[N-] MYFXBBAEXORJNB-UHFFFAOYSA-N 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 150000001767 cationic compounds Chemical class 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
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- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
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- 238000000576 coating method Methods 0.000 description 1
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- 238000006297 dehydration reaction Methods 0.000 description 1
- XXTZHYXQVWRADW-UHFFFAOYSA-N diazomethanone Chemical compound [N]N=C=O XXTZHYXQVWRADW-UHFFFAOYSA-N 0.000 description 1
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- OCQHPGPXSQBVMU-UHFFFAOYSA-N ethyl 2-[2-(4-bromophenyl)-1,3-thiazol-5-yl]acetate Chemical compound S1C(CC(=O)OCC)=CN=C1C1=CC=C(Br)C=C1 OCQHPGPXSQBVMU-UHFFFAOYSA-N 0.000 description 1
- IHAMYSHDXIVMMC-UHFFFAOYSA-N ethyl 2-[4-(4-bromophenyl)-1,3-thiazol-2-yl]acetate Chemical compound S1C(CC(=O)OCC)=NC(C=2C=CC(Br)=CC=2)=C1 IHAMYSHDXIVMMC-UHFFFAOYSA-N 0.000 description 1
- IBHOWDPRDYMIMO-UHFFFAOYSA-N ethyl 3-amino-3-sulfanylidenepropanoate Chemical compound CCOC(=O)CC(N)=S IBHOWDPRDYMIMO-UHFFFAOYSA-N 0.000 description 1
- LJMBLXWCTDYYSB-UHFFFAOYSA-N ethyl 5-[2-(4-bromophenyl)-1,3-thiazol-4-yl]-3-cyano-2-oxopentanoate Chemical compound CCOC(=O)C(=O)C(C#N)CCC1=CSC(C=2C=CC(Br)=CC=2)=N1 LJMBLXWCTDYYSB-UHFFFAOYSA-N 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
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- 235000019634 flavors Nutrition 0.000 description 1
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- 230000037406 food intake Effects 0.000 description 1
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- 239000007789 gas Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 229960001340 histamine Drugs 0.000 description 1
- 235000001050 hortel pimenta Nutrition 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 210000003405 ileum Anatomy 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 229910001411 inorganic cation Inorganic materials 0.000 description 1
- 229960002672 isocarboxazid Drugs 0.000 description 1
- 208000017169 kidney disease Diseases 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- XMGQYMWWDOXHJM-UHFFFAOYSA-N limonene Chemical compound CC(=C)C1CCC(C)=CC1 XMGQYMWWDOXHJM-UHFFFAOYSA-N 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 239000000395 magnesium oxide Substances 0.000 description 1
- CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Inorganic materials [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical compound [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- OSWPMRLSEDHDFF-UHFFFAOYSA-N methyl salicylate Chemical compound COC(=O)C1=CC=CC=C1O OSWPMRLSEDHDFF-UHFFFAOYSA-N 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 239000007968 orange flavor Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- LDTICZAFZSQCJO-UHFFFAOYSA-N pyrrolidine-2,3,5-trione Chemical class O=C1CC(=O)C(=O)N1 LDTICZAFZSQCJO-UHFFFAOYSA-N 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 229960002317 succinimide Drugs 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003451 thiazide diuretic agent Substances 0.000 description 1
- DLFVBJFMPXGRIB-UHFFFAOYSA-N thioacetamide Natural products CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 239000009637 wintergreen oil Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D277/30—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
Definitions
- glycolate oxidase The immediate metabolic precursor of the majority of the oxalate in the urine of a typical patient is glyoxylic acid. In turn its most important precursor is glycolic acid.
- glycolate oxidase is able to carry out the oxidation of glycolic acid, through glyoxylic acid, to oxalic acid. Inhibition of this enzyme will, therefore, reduce the concentration of oxalic acid in the kidney and bladder, reducing the probability that calcium oxalate crystallization will occur.
- inhibitors of glycolate oxidase provide a specific approach to the prevention and treatment of calcium oxalate renal lithiasis.
- Preferred compounds are those wherein
- Still further preferred specific compounds are: and pharmaceutically acceptable salts thereof.
- Glyoxylate is the major immediate forerunner of oxalate.
- An inhibitor of glycolate oxidase (G.O.) will inhibit both the conversion of glyoxylate to oxalate as well as the production of glyoxylate from glycolate.
- Compounds of formula (1) are potent inhibitors of glycolate oxidase and thus are useful in restricting oxalate levels in the blood and urine. Further, they are useful in the treatment and prevention of renal disease due to calcium oxalate stone formation in the kidney and bladder. They may be useful in the treatment of the genetically inherited diseases termed Hyperoxaluria types I and II in which very high levels of metabolic oxalic acid are present.
- the compounds (III) are prepared generally by the method of Fairfull, Lowe and Peak, J. Chem. Soc., 742 (1952).
- the nitrile (II) prepared by known methods, is reacted with an excess of hydrogen sulfide gas in the presence of excess triethylamine in a basic organic solvent such as pyridine.
- a basic organic solvent such as pyridine.
- the thiazole rings (IV) are assembled by the classic Hantzsch procedure using the thioamide (III) and ethyl 4-chloroacetoacetate or its homologs.
- Preparation of the pyrrolinediones from the amides (V) is accomplished by reacting (V) with diethyl oxalate in DMF with strong base such as potassium t-butoxide or sodium ethoxide under an inert atmosphere.
- strong base such as potassium t-butoxide or sodium ethoxide under an inert atmosphere.
- the reaction can also be carried out in alcoholic solvents such as methanol, ethanol and isopropanol with the corresponding alkoxides as base.
- dehydration to the nitrile is carried out by standard methods well known in the art (e.g., with p-toluenesulfonyl chloride in pyridine or thionyl chloride in DMF).
- An alternative route to the nitrile intermediate involves reaction of the thioamide directly with the appropriate halomethylketone-substituted alkyl cyanide. Reaction of the nitrile with diethyl oxalate in the presence of base (usually sodium or potassium alkoxide in solvents such as methanol, ethanol, dimethylformamide, or toluene at room temperature to 60°C) provides the intermediate 3-cyano-2- keto acid ester.
- base usually sodium or potassium alkoxide in solvents such as methanol, ethanol, dimethylformamide, or toluene at room temperature to 60°C
- Cyclization to the hvdroxypyrrolinedione (I) is carried out by reaction first in strong acid, such as sulfuric or methanesulfonic acid for several hours to overnight, and then mixing the solution with ethanol containing 5-10% water. Evaporation of the ethanol and extraction with chloroform or ethyl acetate provides the desired 3-hydroxy-3-pyrroline-2,5-dione product.
- the sulfuric or methanesulfonic acid solutions may be quenched with ice-water.
- the nitrile intermediate may be first converted to the imino ether with cold HCI in ethanol.
- the imino ether when heated in chloroform, is converted to the hydroxypyrrolinedione (I).
- the bromomethyl ketone intermediate is reacted with the appropriate ethoxycarbonyl- alkylthioamide in refluxing ethanol to form the 4-substituted-2-thiazolylalkanoic acid ethyl ester which is converted to the amide and subsequently to the hydroxypyrrolinedione derivative by the procedures outlined above.
- the compounds of formula are strong organic acids with a pKa in the range 2-4. These salts are readily formed with the usual inorganic cations such as sodium, potassium and ammonium. Salts with organic amines such as trimethylamine, triethylamine, n-butylamine and the like are also very stable.
- the neutralization can be carried out by a variety of procedures known to the art to be generally useful for the preparation of such salts. The choice of the most suitable procedure will depend on a variety of factors including convenience of operation, economic considerations, and particularly the solubility characteristics of the particular free base, the acid, and the acid addition salt.
- the compounds of formula (I) are utilized for the stated utilities by formulating them in a composition such as tablet, capsule or elixir for oral administration. Sterile solutions or suspensions can be used for parenteral administration. About 10 to 200 mg of the compound of formula (I) or a physiologically acceptable salt is compounded with a physiologically acceptable vehicle, carrier, excipient, binder, preservative, stabilizer, flavor, etc., in a unit dosage form as called for by accepted pharmaceutical practice. The amount of active substance in the composition is such that dosage in the range indicated is obtained. The total daily dose will be in the 30 to 2000 mg range and preferably in the range of 50 mg. to 1000 mg.
- Illustrative of the adjuvants which may be incorporated in tablets, capsules and the like are the following: a binder such as gum tragacanth, acacia, corn starch or gelatin; and excipient such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; a sweetening agent such as sucrose, lactose, or saccharin; a flavouring agent such as peppermint, oil of wintergreen or cherry.
- a liquid carrier such as a fatty oil.
- tablets may be coated with shellac, sugar or the like.
- a syrup or elixir may contain the active compound, sucrose as a sweetening agent, methyl and propyl parabens as preservatives, a dye and a flavouring such as cherry or orange flavor.
- Sterile compositions for injection can be formulated according to conventional pharmaceutical practice by dissolving or suspending the active substance in a conventional vehicle such as water for injection, a naturally occurring vegetable oil like sesame oil, coconut oil, peanut oil, cottonseed oil, etc., or a synthetic fatty vehicle like ethyl oleate or the like. Buffers, preservatives, antioxidants and the like can be incorporated as required.
- the extract was washed with water (2 x 100 ml), dried (MgS0 4 ) and evaporated to a semi-solid which contained the desired ester and the corresponding acid.
- the mixture was dissolved in ethanol (100 ml) saturated with hydrogen chloride and the solution was allowed to stand at room temperature for 1 day. The solution was evaporated to dryness and the ester was used without further purification for preparing the amide.
- a mixture of the substituted acetamide (10 mmoie), diethyl oxalate (1.533 g, 10.5 mmole) and dry dimethylformamide (20 ml) is stirred under nitrogen or argon and cooled in an ice-bath.
- Potassium t-butoxide (2.464 g, 22 mmole) is added in two equal portions 15 minutes apart and the reaction mixture is stirred for about 30 minutes in the ice-bath and then at room temperature overnight.
- the reaction mixture is poured into ice-water (100 ml).
- the aqueous mixture is extracted with ethyl acetate (2 x 35 ml) and then acidified with 6N hydrochloric acid in order to precipitate the product.
- the product is either collected by filtration or by extraction with ethyl acetate.
- the potassium salt is not soluble when the reaction mixture is quenched in ice-water, then it is necessary to acidify the resulting suspension and collect the product by filtration.
- the crude product is generally less pure when obtained in this way.
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Reproductive Health (AREA)
- Urology & Nephrology (AREA)
- Endocrinology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Thiazole And Isothizaole Compounds (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Plural Heterocyclic Compounds (AREA)
Claims (9)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AT80105409T ATE2271T1 (de) | 1979-09-11 | 1980-09-10 | 4-(substituierte thiazolyl)-3-hydroxy-3-pyrrolin2,5-dion-verbindungen, verfahren zur herstellung und sie enthaltende pharmazeutische zusammensetzung. |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US06/074,465 US4298743A (en) | 1979-09-11 | 1979-09-11 | 4-(Substituted phenyl thiazolyl)-3-hydroxy-3-pyrroline-2,5-diones |
US74465 | 1979-09-11 |
Publications (2)
Publication Number | Publication Date |
---|---|
EP0025232A1 EP0025232A1 (de) | 1981-03-18 |
EP0025232B1 true EP0025232B1 (de) | 1983-01-19 |
Family
ID=22119703
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP80105409A Expired EP0025232B1 (de) | 1979-09-11 | 1980-09-10 | 4-(Substituierte Thiazolyl)-3-hydroxy-3-pyrrolin-2,5-dion-Verbindungen, Verfahren zur Herstellung und sie enthaltende pharmazeutische Zusammensetzung |
Country Status (9)
Country | Link |
---|---|
US (1) | US4298743A (de) |
EP (1) | EP0025232B1 (de) |
JP (1) | JPS5646809A (de) |
AT (1) | ATE2271T1 (de) |
DE (1) | DE3061688D1 (de) |
DK (1) | DK384280A (de) |
ES (1) | ES8105996A1 (de) |
GR (1) | GR70200B (de) |
PT (1) | PT71755B (de) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7144911B2 (en) | 2002-12-31 | 2006-12-05 | Deciphera Pharmaceuticals Llc | Anti-inflammatory medicaments |
US7202257B2 (en) | 2003-12-24 | 2007-04-10 | Deciphera Pharmaceuticals, Llc | Anti-inflammatory medicaments |
Families Citing this family (29)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4379791A (en) * | 1979-09-11 | 1983-04-12 | Merck & Co., Inc. | 4-(Substituted thiazolyl)-3-hydroxy-3-pyrroline-2,5-dione inhibitors of glycolic acid oxidase |
US4700901A (en) * | 1985-08-19 | 1987-10-20 | Breville R & D Pty. Limited | Food processors |
WO1992009586A1 (en) * | 1990-11-30 | 1992-06-11 | Otsuka Pharmaceutical Co., Ltd. | Active oxygen inhibitor |
MY128323A (en) * | 1996-09-30 | 2007-01-31 | Otsuka Pharma Co Ltd | Thiazole derivatives for inhibition of cytokine production and of cell adhesion |
US6313156B1 (en) | 1999-12-23 | 2001-11-06 | Icos Corporation | Thiazole compounds as cyclic-AMP-specific phosphodiesterase inhibitors |
DE10029077A1 (de) * | 2000-06-13 | 2001-12-20 | Bayer Ag | Thiazolylsubstituierte Heterocyclen |
EP1422218B1 (de) * | 2001-08-10 | 2012-03-21 | Shionogi & Co., Ltd. | Antivirales mittel |
US6858615B2 (en) | 2002-02-19 | 2005-02-22 | Parion Sciences, Inc. | Phenyl guanidine sodium channel blockers |
US6858614B2 (en) * | 2002-02-19 | 2005-02-22 | Parion Sciences, Inc. | Phenolic guanidine sodium channel blockers |
US7279576B2 (en) | 2002-12-31 | 2007-10-09 | Deciphera Pharmaceuticals, Llc | Anti-cancer medicaments |
US6903105B2 (en) | 2003-02-19 | 2005-06-07 | Parion Sciences, Inc. | Sodium channel blockers |
US7745442B2 (en) | 2003-08-20 | 2010-06-29 | Parion Sciences, Inc. | Methods of reducing risk of infection from pathogens |
WO2006071940A2 (en) | 2004-12-23 | 2006-07-06 | Deciphera Pharmaceuticals, Llc | Enzyme modulators and treatments |
US8188113B2 (en) | 2006-09-14 | 2012-05-29 | Deciphera Pharmaceuticals, Inc. | Dihydropyridopyrimidinyl, dihydronaphthyidinyl and related compounds useful as kinase inhibitors for the treatment of proliferative diseases |
US7790756B2 (en) | 2006-10-11 | 2010-09-07 | Deciphera Pharmaceuticals, Llc | Kinase inhibitors useful for the treatment of myleoproliferative diseases and other proliferative diseases |
BRPI0807717A2 (pt) | 2007-04-20 | 2014-05-20 | Deciphera Pharmaceuticals Llc | Inibidores de quinase úteis para o tratamento de doenças mieloproliferativas e outras doenças proliferativas. |
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Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
BE599556A (de) * | 1960-02-01 | |||
US3340263A (en) * | 1964-02-14 | 1967-09-05 | Ciba Geigy Corp | Amino-pyrroles |
GB1127875A (en) * | 1967-03-23 | 1968-09-18 | Parke Davis & Co | 4-(5-nitro-2-furyl) thiazolyl hydantoins and hydrouracils |
GB1304174A (de) * | 1969-03-07 | 1973-01-24 |
-
1979
- 1979-09-11 US US06/074,465 patent/US4298743A/en not_active Expired - Lifetime
-
1980
- 1980-08-29 PT PT71755A patent/PT71755B/pt unknown
- 1980-09-08 GR GR62835A patent/GR70200B/el unknown
- 1980-09-10 EP EP80105409A patent/EP0025232B1/de not_active Expired
- 1980-09-10 DE DE8080105409T patent/DE3061688D1/de not_active Expired
- 1980-09-10 AT AT80105409T patent/ATE2271T1/de not_active IP Right Cessation
- 1980-09-10 ES ES494933A patent/ES8105996A1/es not_active Expired
- 1980-09-10 DK DK384280A patent/DK384280A/da not_active Application Discontinuation
- 1980-09-11 JP JP12536980A patent/JPS5646809A/ja active Pending
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7144911B2 (en) | 2002-12-31 | 2006-12-05 | Deciphera Pharmaceuticals Llc | Anti-inflammatory medicaments |
US7342037B2 (en) | 2002-12-31 | 2008-03-11 | Deciphera Pharmaceuticals, Llc | Anti-inflammatory medicaments |
US7666895B2 (en) | 2002-12-31 | 2010-02-23 | Deciphera Pharmaceuticals, Llc | Anti-inflammatory medicaments |
US7737283B2 (en) | 2002-12-31 | 2010-06-15 | Deciphera Pharmaceuticals, Llc | Anti-inflammatory medicaments |
US7202257B2 (en) | 2003-12-24 | 2007-04-10 | Deciphera Pharmaceuticals, Llc | Anti-inflammatory medicaments |
Also Published As
Publication number | Publication date |
---|---|
ES494933A0 (es) | 1981-07-01 |
JPS5646809A (en) | 1981-04-28 |
DK384280A (da) | 1981-03-12 |
ATE2271T1 (de) | 1983-02-15 |
DE3061688D1 (en) | 1983-02-24 |
US4298743A (en) | 1981-11-03 |
GR70200B (de) | 1982-08-31 |
ES8105996A1 (es) | 1981-07-01 |
PT71755B (en) | 1982-03-19 |
PT71755A (en) | 1980-09-01 |
EP0025232A1 (de) | 1981-03-18 |
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